The incidence of thyroid cancer has more than doubled in the last 30 years with nearly 50% of this increase attributable to papillary microcarcinomas (PMC). Despite compeling evidence that cautious observation is a safe and effective alternative to immediate surgical resection, very few PMC patients in the United States are given the option of an active surveillance approach. This is in part due to reports in the literature of a small percentage of patients with PMC that develop loco-regional or distant metastases. Unfortunately, neither clinical features, nor the mutational status ofthe known thyroid cancer oncogenes reliably identify the few PMC patients destined to develop clinically significant disease progression. Since only a small minority of PMC progress to clinically significant disease, it is imperative that we critically re-evaluate the current management paradigm that indiscriminately recommends immediate surgical intervention without giving patients an option for active surveillance. We propose to use both paraffin embedded tissue samples from our pathology archives and fresh frozen PMC samples obtained after 2-5 years of observation in a prospective active surveillance trial to identify molecular events that are predictive of disease progression through a comprehensive evaluation of the PMC cancer genome using massively parallel next generation exon sequencing of 230 genes commonly mutated in cancer coupled to quantitative expression profiling using a custom-designed NanoString platform. Our goal is to identify genomic predictors of disease progression in PMC so that tumors likely to develop into clinically significant disease can be surgically removed, whereas the vast majority that are unlikely to grow or metastasize can be followed with periodic surveillance. Aim 1: To perform indepth genomic profiling of PMCs without metastatic disease compared to PMCs with loco-regional and/or distant metastasis. Aim 2: To identify genomic predictors of disease progression in a prospectively followed population of patients with PMC.